Human immunodeficiency virus (HIV) is a human retrovirus which causes a series of diseases such as acquired immunodeficiency syndrome (AIDS) and AIDS related complexes (ARC). Today, these diseases have become a serious problem in the world, but no vaccines or established therapies effective for these diseases have been provided.
As an anti-viral agent against HIV, reverse transcriptase inhibitors of nucleic acid analogues such as 3'-azido-2', 3'-dideoxythymidin (AZT) or 2',3'-dideoxyinosin (ddI) have been used, and thereby therapeutic efficacy such as inhibition of viral growth, increase in the number of CD4-positive cells and prolongation of life span has been observed. However, in most cases, therapeutic efficacy of these drugs to AIDS is partial or temporal, and in addition, these drugs exhibit toxicity or growth inhibition to hematopoietic cells, and thereby inhibit reconstruction of an immune system which has become deficient. From these points of view, development of more effective anti-HIV agents has been desired.
An antibody is an important protein which plays a role in an immune reaction in mammals including humans and has a function to neutralize and remove foreign substances invaded from outside or substances recognized as foreign substances by the living body. In this respect, an antibody is expected to be useful for treatment of infectious diseases.
Karpas et al. observed remission of clinical symptoms after administration of anti-HIV antibodies derived from healthy patients infected with HIV to AIDS patients (Proc. Natl. Acad. Sci. USA, 85, p.9234 (1989), Proc. Natl. Acad. Sci. USA, 87, p. 7613 (1990)). Jackson et al. also obtained similar results (Lancet, 2, p. 647 (1988)). These results show usefulness of an antibody therapy in AIDS.
Apart from such passive immunotherapy, an active immunization of patients with a component vaccine of HIV has also been attempted in order to enhance immune capacity (AIDS Res. Hum. Retroviruses, 8, P1051 (1992)). This treatment was found to be effective to patients who have not yet developed symptoms, but did not show significant effect in patients who developed AIDS with a decreased number of CD4-positive cells since they are deficient in active immune response. Accordingly, in case of those patients whose disease has progressed, one cannot but rely on passive immunotherapy, and hence, a neutralizing antibody has a great significance.
Epitopes recognized by an antibody neutralizing HIV are located in a glycoprotein antigen having a molecular weight of about 1.2.times.10.sup.5 daltons (gp120) present on a coating membrane of HIV, a transmembrane glycoprotein antigen having a molecular weight of about 4.1.times.10.sup.4 daltons (gp41) and a nuclear protein antigen having a molecular weight of about 1.7.times.10.sup.4 daltons (p17). Among these epitopes, that located in the third variable region (V3) of gp120(amino acid number 303-338), which is also referred to as Principal Neutralization Determinant (PND), can induce a potent neutralizing antibody, and hence, is a major target in developing medicaments or vaccines.
Although a correct role of PND region in viral infection remains still unknown, it is assumed to help invasion of viruses after binding between gp120 and CD4. PND region also plays an important role in formation of multinuclear giant cells by CD4-positive cells. Accordingly, if an antibody which binds to this region and inhibits infection and growth of viruses is prepared, this can possibly be an effective anti-HIV agent.
However, since PND region shows a high variability in amino acid sequence as compared to other epitopes in gp120, most of monoclonal antibodies which recognize this region are viral strain-specific neutralizing antibody which recognizes only a specific HIV strain. If such strain-specific monoclonal antibody is used for treatment or prevention, its efficacy is restricted to those patients who are infected with HIV strain that can be neutralized with that antibody. Furthermore, in a individual HIV-infected patient, HIV is never present as a single HIV strain but usually as quasispecies of many HIV variants whose amino acid sequence show several % variation.
Therefore, possibility of a monoclonal antibody as a medicament is closely related to what extent of many HIV variants present in patients or within a single patient said antibody can bind to and neutralize, i.e. a range of neutralization spectrum of antibody. In order to obtain a clinically useful HIV medicament, a monoclonal antibody having as broad neutralization spectrum as possible is preferably established.